Glycosaminoglycans alter the capacity of low density lipoprotein to bind to monosodium urate crystals.
Low density lipoprotein (LDL) has previously been demonstrated to be a potent inhibitor of human inflammatory cell activation by monosodium urate (MSU) crystals in vitro. As suppression of cellular responses to crystals by LDL is known to be dependent on the binding of LDL to urate crystals we further evaluated the mechanism and regulation of LDL binding to urate crystals in vitro. Using nonlinear, least squares methodology to analyze binding, we found LDL to saturably and reversibly bind with high affinity (Kd 9.3 x 10(-9) M) to MSU crystals. LDL binding was competitively inhibited by LDL but not by a variety of other positively charged moieties. Glycosaminoglycans (GAG) (heparin, heparan sulfate, hyaluronate and chondroitin sulfate), in diminishing order of potency, inhibited the binding of LDL to crystals. This inhibitory activity was dose dependent, sensitive to digestion with glycosidases and appeared to be specific for polymerized GAG, as glucuronic acid, dextran, dextran sulfate, as well as isolated amino sugar constituents of GAG were either weakly inhibitory or inactive. GAG also promoted dissociation of bound LDL from the urate crystal surface. The results indicate that LDL binds saturably and reversibly to urate crystals and that polymerized, but not depolymerized, hyaluronate and other GAG inhibit LDL binding to urate crystals. This suggests that the amount of LDL coating intraarticular urate crystals could vary during the course of a gouty paroxysm.
Terkeltaub
R
R
VA Medical Center, San Diego, CA 92161.
Martin
J
J
Curtiss
L K
LK
Ginsberg
M H
MH
D003460:Crystallization; D004305:Dose-Response Relationship, Drug; D005340:Fibrinogen / Q000494:pharmacology; D006025:Glycosaminoglycans / Q000494:pharmacology*; D006801:Humans; D006820:Hyaluronic Acid / Q000494:pharmacology; D007074:Immunoglobulin G / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects*; D014527:Uric Acid / Q000378:metabolism*
D006025:Glycosaminoglycans; D007074:Immunoglobulin G; D008077:Lipoproteins, LDL; D014527:Uric Acid; D005340:Fibrinogen; D006820:Hyaluronic Acid